Homozygous W748S mutation in the <i>POLG1</i> gene in patients with juvenile‐onset Alpers syndrome and status epilepticus

Uusimaa, Johanna; Hinttala, Reetta; Rantala, Heikki; Päivärinta, Markku; Herva, Riitta; Röyttä, Matias; Soini, Heidi K.; Moilanen, Jukka S.; Remes, Anne M.; Hassinen, Ilmo E.; Majamaa, Kari

doi:10.1111/j.1528-1167.2008.01544.x

Cited by 77 publications

(79 citation statements)

References 39 publications

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“…The younger brother of this girl has a slight developmental retardation but no other symptoms at his current age of 3 years. These observations are consistent with previous reports that patients homozygous for the W748S mutation have a milder disease with onset in later childhood or even adult age (Uusimaa et al 2008). The patient we report here has one deleted POLG1 allele and the W748S mutation on the retained POLG1 allele.…”

Section: Discussionsupporting

confidence: 93%

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Complete Deletion of a POLG1 Allele in a Patient with Alpers Syndrome

et al. 2011

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Section: Discussionsupporting

confidence: 93%

“…Additional symptoms such as ataxia, hypotonia, and cortical blindness are frequently seen (McFarland et al 2008). Onset is usually in early childhood, although later forms exist (Uusimaa et al 2008). Skeletal muscle is not always affected and a muscle biopsy often turns out to be normal in children with Alpers syndrome.…”

Section: Discussionmentioning

confidence: 99%

Complete Deletion of a POLG1 Allele in a Patient with Alpers Syndrome

et al. 2011

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“…Early in the course of epilepsy, seizures are often controlled with conventional medications. However, as the disease progresses, the seizures become increasingly resistant to valproic acid and other medications that trigger liver failure (Bicknese et al 1992;Engelsen et al 2008;Uusimaa et al 2008;Wolf et al 2009;. Even without .…”

Section: Alpers-huttenlocher Syndrome (Ahs)mentioning

confidence: 99%

Clinical and Molecular Features of POLG-Related Mitochondrial Disease

Stumpf

Saneto

Copeland

2013

Cold Spring Harbor Perspectives in Biology

117

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“…Biochemically, this has been noted as some patients have demonstrated reductions in Complexes I-IV and pyruvate dehydrogenase in muscle [de Vries et al, 2007]. Unfortunately, muscle analysis of electron transport chain activity, may or may not show abnormalities [GonzalezVioque et al, 2006;Kollberg et al, 2006;Milone et al, 2008;Uusimaa et al, 2008;Saneto et al, 2010]. The lack of definite electron transport chain abnormalities in some patients is not clear; there are many reasons one can think of, including early muscle biopsy before abnormalities due to mtDNA depletion can be seen.…”

Section: Biochemical Aspects Of Polg Diseasementioning

confidence: 94%

Polymerase gamma disease through the ages

Saneto

Naviaux

2010

Dev Disabil Res Revs

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The most common group of mitochondrial disease is due to mutations within the mitochondrial DNA polymerase, polymerase gamma 1 (POLG). This gene product is responsible for replication and repair of the small mitochondrial DNA genome. The structure-function relationship of this gene product produces a wide variety of diseases that at times, seems to defy the common perceptions of genetics. The unique features of mitochondrial physiology are in part responsible, but POLG structure and function add to the conundrum of how one gene product can demonstrate autosomal recessive and autosomal dominant transmission, while also being responsible for pharmacogenetic disease, and exhibiting strong gene-environment interactions. The wide spectrum of clinical manifestations of POLG disease can arise from infancy to old age. The modulation of clinical findings relate in part to the molecular architecture of the POLG protein. POLG has three distinct molecular domains: exonuclease, linker, and polymerase domains. Most of the mutations leading to dominant forms of POLG disease are located in the Polymerase domain. Mutations leading to recessive inheritance are distributed in all three domains of the gene. Environmental factors like valproic acid and infection can unmask POLG disease, causing it to occur earlier in life than when not exposed to these factors. Other drugs like nucleoside reverse transcriptase inhibitors can produce genotype-specific POLG pharmacogenetic disease. Our current state of POLG understanding cannot account for many features of POLG disease. There is no answer for why the same mutation can give rise to varying diseases, disease severity, and age of onset. We introduce the term Ecogenetics in the context these features of POLG disease, to emphasize the important interactions between genes and environment in determining the expression of mitochondrial disease. In this article, we identify some of the key features that will help the reader understand POLG pathophysiology. When possible, we also identify genotype-phenotype relationships, give clues for diagnosis, and summarize the major clinical phenotypes in the spectrum of POLG disease presenting from birth to old age.

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Homozygous W748S mutation in the POLG1 gene in patients with juvenile‐onset Alpers syndrome and status epilepticus

Cited by 77 publications

References 39 publications

Complete Deletion of a POLG1 Allele in a Patient with Alpers Syndrome

Complete Deletion of a POLG1 Allele in a Patient with Alpers Syndrome

Clinical and Molecular Features of POLG-Related Mitochondrial Disease

Polymerase gamma disease through the ages

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